Pharmacoeconomics of prophylactic, empirical, and diagnostic-based antibiotic treatments
Purba, Abdul
DOI:
10.33612/diss.128518764
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Purba, A. (2020). Pharmacoeconomics of prophylactic, empirical, and diagnostic-based antibiotic
treatments: Focus on surgical site infection and hospitalized community-acquired pneumonia. University of Groningen. https://doi.org/10.33612/diss.128518764
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empirical, and diagnostic-based
antibiotic treatments
Focus on surgical site infection and
hospitalized community-acquired pneumonia
Author: Abdul Khairul Rizki Purba
Cover: Abdul Khairul Rizki Purba (concept) and zannoism.com (design)
Lay-out: Douwe Oppewal
Printing: Ipskamp Printing, Enschede
ISBN (book): 978-94-034-2805-5
ISBN (electronic version): 978-94-034-2806-2
This thesis was funded by grants from DIKTI BPPLN scholarship (the scholarship from Directorate General of Resources for Science, Technology and Higher Education, Ministry of Research, Technology and Higher Education, Republic of Indonesia), from Universitas Airlangga, and from the University Medical Center Groningen, the Netherlands. Also, the work presented in this thesis was performed at the Department of Health Sciences and the Department of Medical Microbiology of the University Medical Center Groningen. Financial support for printing this thesis was kindly provided by the University of Groningen and the Groningen University for Drug Exploration (GUIDE) of the Graduate School of Medical Sciences (GSMS).
Copyright, 2020, Abdul Khairul Rizki Purba
All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means, electronically or mechanically by photocopying, recording, or otherwise, without written permission of the author. The copy right of previously published chapters of this thesis remains with the publisher or journal.
Pharmacoeconomics of
prophylactic, empirical, and
diagnostic-based antibiotic
treatments
Focus on surgical site infection and hospitalized
community-acquired pneumonia
PhD thesis
to obtain the degree of PhD at the
University of Groningen
on the authority of the
Rector Magnificus Prof. C. Wijmenga
and in accordance with
the decision by the College of Deans.
This thesis will be defended in public on
Wednesday 8 July 2020 at 12.45 hours
by
Abdul Khairul Rizki Purba
Focus on surgical site infection and hospitalized community-acquired pneumonia
Author: Abdul Khairul Rizki Purba
Cover: Abdul Khairul Rizki Purba (concept) and zannoism.com (design)
Lay-out: Douwe Oppewal
Printing: Ipskamp Printing, Enschede
ISBN (book): 978-94-034-2805-5
ISBN (electronic version): 978-94-034-2806-2
This thesis was funded by grants from DIKTI BPPLN scholarship (the scholarship from Directorate General of Resources for Science, Technology and Higher Education, Ministry of Research, Technology and Higher Education, Republic of Indonesia), from Universitas Airlangga, and from the University Medical Center Groningen, the Netherlands. Also, the work presented in this thesis was performed at the Department of Health Sciences and the Department of Medical Microbiology of the University Medical Center Groningen. Financial support for printing this thesis was kindly provided by the University of Groningen and the Groningen University for Drug Exploration (GUIDE) of the Graduate School of Medical Sciences (GSMS).
Copyright, 2020, Abdul Khairul Rizki Purba
All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means, electronically or mechanically by photocopying, recording, or otherwise, without written permission of the author. The copy right of previously published chapters of this thesis remains with the publisher or journal.
Co-supervisor
Dr. J.W. Dik
Assessment Committee
Prof. Kuntaman
Prof. B. Wilffert
Prof. J.C. Wilschut
Part 1. Introduction 11
Chapter 1 General introduction 13
Chapter 2 The burden and costs of sepsis and reimbursement of its treatment in
a developing country: An observational study on focal infections in Indonesia 21 Part 2. Prophylactic antibiotics for surgical site infection prevention 43
Chapter 3 Prevention of surgical site infections: A systematic review of cost analyses
in the use of prophylactic antibiotics 45
Chapter 4 The impacts of deep surgical site infections on readmissions, length of stay,
and costs: A matched case-control cohort study in an academic hospital
in the Netherlands 81
Part 3. Empirical antibiotics for hospitalized
community-acquired pneumonia 97
Chapter 5 Multidrug-resistant infections among hospitalized adults with
community-acquired pneumonia in an Indonesian tertiary referral hospital 99
Chapter 6 Cost-effectiveness of culture-based versus empirical antibiotic treatment
for hospitalized adults with community-acquired pneumonia in Indonesia:
A real-world patient-database study 119
Part 4. Discussion 143
Chapter 7 General discussion and future perspectives 145
Chapter 8 Appendix: Laboratory findings as predictors of sepsis mortality
among adult patients in a general hospital in Indonesia 155
Addendum 163 Summary 164 Samenvatting 168 Ringkasan 172 Acknowledgments 176 Curriculum vitae 185 List of publications 189 Biography 190
1
Part
Introduction
CHAPTER 1
INTRODUCTION
Surgical site infection (SSI) and hospitalized community-acquired pneumonia (CAP) reflect two infectious conditions caused by bacterial infections. The focal infections underlying SSI and hospitalized CAP can develop into further advanced complications with manifestations of systemic infection symptoms such as sepsis, with pathogens spreading into the blood circulation and organs. Specific situations require antibiotics for prophylactic and/or empirical treatments. Potentially, sometimes antibiotics are being used improperly and ineffectively, leading to further impacts such as antimicrobial resistance (AMR) with a related burden in terms of morbidity, mortality, and cost, especially in developing countries.1,2 Diagnostic-based antibiotic treatments are the potential solution to reduce such unguided antibiotic treatments. Ergo, there is a need for careful analysis of infections, its treatment and AMR, both in the developed world like The Netherlands as well as in the developing world like in Indonesia. This thesis aims to address this issue in both settings, with a focus on pharmacoeconomic aspects.
Among limited-resource countries, Indonesia has a documented low application of pharmacoeconomics in infectious disease treatments.3,4 Such assessment is needed to provide adequate evidence and contribute to Indonesian national government policy strategies, with the pharmacoeconomics approach being used to evaluate the treatment and diagnostic bundles within a restricted budget setting. In addition to pharmacoeconomics assessments of infection treatments, medical microbiology evaluations are essential in order to develop strategies to prevent increased antibiotic resistance by identifying the specific characteristics of the underlying pathogens causing the infections. In this thesis, we illustrate this approach with data, figures analyses for SSI and hospitalized CAP.
The surgical site is a potential port of entry for exogenous organisms: these pose an immediate threat to the body, and infections cause prolonged wound healing.5,6 SSI is the most common focal infection related to surgery and an important target for infectious disease prevention.6,7 In low and middle-income countries, SSI rates in 100 surgical patients doubled from 5.6 to 11.8 between 1995 and 2008.8 Antiseptic and prophylactic antibiotics used properly in the preoperative phase should be considered to prevent SSI. Parenteral and oral antibiotic prophylaxis based on the patterns of bacteria and antibiotic susceptibility has been recommended recently to reduce SSI rates efficiently.5 The most crucial goal in the preoperative preparation period is to reduce the bacterial load surrounding the incision area.9,10 Various modalities have been implemented, ranging from the prevention of SSI using a prophylactic antibiotic before surgical incision and in the postoperative period.10–12 The World Health Organization (WHO) has released guidelines on preventing SSI by assessing prophylactic antibiotics in three consecutive periods: preoperative, intraoperative and postoperative. Broad utilization of prophylactic antibiotics, however, comes with the potential danger of improper use and leads to repercussions such as readmission and additional cost. Economic analysis of prophylactic antibiotic use can help in guiding adequate SSI prevention. Given its resource-limited setting, Indonesia has employed the limited bundle for SSI prevention adopting four out of the 21 WHO measures (Figure 1.1).10,13 As yet, there has been no integrated efficacy and cost assessment of antibiotic prophylaxis for SSI prevention in Indonesia.
Figure 1.1 The measures for preoperative, intraoperative, and postoperative care to prevent surgical site infections.10
Note: *These four measures have been considered in Indonesia for SSI prevention.13
Hospitalized CAP is a non-surgical-related infectious disease, contributing high morbidity in terms of more hospitalizations for ICU admissions, requiring mechanical ventilators and further sepsis complication.14–16 Elevated hospitalization costs for ICU patients with CAP were strongly associated with the use of a mechanical ventilator, the presence of severe sepsis and sepsis shock.17 According to information from the Centers for Disease Control and Prevention (CDC) in Indonesia, lower respiratory tract infections (LRTIs) reflected the most common cause of death among infectious disease cases.18 Among LRTIs in Indonesia, CAP has been reported with an incidence rate of 4% in 2018.19,20 CAP can pose challenges in treatment and primary healthcare providers, especially in a limited-resource setting such as Indonesia, frequently refer moderate and severe CAP cases to hospitals that have more comprehensive facilities. Hospitalization is often required for cases with underlying bacterial infections and to need at least one empirical antibiotic.21–25
Table 1.1 Microorganisms causing hospitalized community-acquired pneumonia in Indonesia, based on a local survey between 1989 and 2001 in Surabaya, Medan, and Makasar26
Microorganisms n % Klebsiella pneumoniae 85 21.5% Streptococcus pneumoniae 51 12.9% Staphylococcus aureus 39 9.8% Streptococcus β haemolyticus 35 8.8% Staphylococcus epidermidis 27 6.8% Streptococcus viridans 25 6.3% Streptococcus pyogenes 21 5.3% Enterobacter aerogenous 19 4.8% Proteus vulgaris 18 4.5% Pseudomonas aeruginosa 15 3.8% Candida albican 12 3.0%
Streptococcus gamma haemolyticus 7 1.8%
Klebsiella oxytoca 7 1.8% Escherichia coli 7 1.8% Staphylococcus albus 7 1.8% Klebsiella ozainae 6 1.5% Proteus mirabillis 6 1.5% Enterobacter agglomerans 3 0.8% Peptostreptococcus spp. 2 0.5% Streptococcus faecalis 2 0.5% Candida parapsilosis 2 0.5%
Note: Adapted from Indonesian Society of Respirology, Guideline for diagnosis and management of community-acquired pneumonia in Indonesia [Perhimpunan Dokter Paru Indonesia. Pneumonia Komuniti: pedoman diagnosis dan penatalaksanaan di Indonesia]. 2003. Available from https://www.klikpdpi.com/
With the increasing problem of AMR, guidelines for antibiotic use are needed. Underlying such guidelines should be updated antimicrobial resistance data and data on treatment efficacy, for example, supporting new national guidelines on the empirical use of antibiotics can be put forward. Table 1.1 shows the underlying pathogens causing hospitalized CAP in three big cities in Indonesia. The current Indonesian guidelines on hospitalized CAP treatment have been developed in 2003, following the American Thoracic Society (ATS) guidelines.23,25 These guidelines, however, were based on studies conducted in 1991-2001 in high-income countries where Streptococcus pneumoniae and some Gram-positive bacteria were the most dominant pathogens causing CAP.27 The guidelines, therefore, recommend selecting antibiotics that are particularly effective to Gram-positive bacteria.23 In contrast, among the pathogens causing CAP in Indonesia, Gram-negative bacteria are considered to be the most common underlying
pathogen.28,29 Indiscriminate use of antimicrobials as a result of unrepresentative guidelines, not guided by local/national microbiological evidence, generally results in the increasing emergence of antimicrobial resistance, both in individual patients and at the community level.
SCOPE OF THE THESIS
The main focus of this thesis is to assess pharmacoeconomic aspects in the management of bacterial infections; applied to illustrative cases, namely, SSI and hospitalized CAP. Chapter 2 presents a discussion of the burden of two conditions concerning sepsis related to various focal infections. This chapter also puts forward a proposed national unit price taking into account the cost of focal infections with sepsis with universal health coverage now being introduced in Indonesia. Focusing on the use of prophylactic antibiotics for SSI prevention, Chapter 3 reviews the methodologies used in published economic evaluations on prophylactic antibiotics in SSI prevention. The review also includes a comprehensive discussion of the local epidemiology of pathogen-causing SSIs. In addition, Chapter 4 discusses the impact of surgical site infections on readmissions and costs in an academic hospital in the Netherlands. This potentially provides a prospective model for developing a health policy on implementation strategies to tackle SSI cases in Indonesia as the Dutch model may be conceived as being successful. For example, the European Centre for Disease Prevention and Control’s point prevalence surveys in 2016 and 2017 documented that the Netherlands successfully decreased SSI incidence from 2.2 to 1.0 per 100 surgeries.30,31 Focusing on the use of empirical antibiotics versus diagnostic-based antibiotic treatment, Chapter 5 outlines the clinical epidemiology of multidrug-resistant infections among hospitalized adults with CAP in an Indonesian tertiary referral hospital. Chapter 6 analyzes the cost-effectiveness of culture-based versus empirical antibiotic treatment for hospitalized adults with CAP in Indonesia, based on a real-world patient database study. Finally, Chapter 7 discusses the main findings presented in the previous chapters and makes several recommendations, particularly for institutions or policymakers who are currently facing uncertainty about bundling SSI and hospitalized CAP sepsis in healthcare management due to the excessive cost in a limited-resource setting. As an Annex to Chapter 7 additional clinical evidence on laboratory biomarkers as independent factors to sepsis mortality is presented in Chapter 8.
REFERENCES
1. Azmi, S. et al. Assessing the burden of pneumonia using administrative data from Malaysia, Indonesia, and the Philippines.
Int. J. Infect. Dis. 49, 87–93 (2016).
2. Ling, M. L., Apisarnthanarak, A. & Madriaga, G. The Burden of Healthcare-Associated Infections in Southeast Asia: A Systematic Literature Review and Meta-analysis. Clin. Infect. Dis. 60, 1690–1699 (2015).
3. Teerawattanasook, N. et al. Capacity and Utilization of Blood Culture in Two Referral Hospitals in Indonesia and Thailand.
Am. J. Trop. Med. Hyg. 97, 1257–1261 (2017).
4. Babar, Z.-U.-D. & Scahill, S. Is there a role for pharmacoeconomics in developing countries? Pharmacoeconomics 28, 1069– 1074 (2010).
5. Berrios-Torres, S. I. et al. Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017. JAMA Surg. 152, 784–791 (2017).
6. Mangram, A. J., Horan, T. C., Pearson, M. L., Silver, L. C. & Jarvis, W. R. Guideline for Prevention of Surgical Site Infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am. J. Infect.
Control 27, 97–132; quiz 133–4; discussion 96 (1999).
7. Merkow, R. P. et al. Underlying reasons associated with hospital readmission following surgery in the United States. JAMA 313, 483–495 (2015).
8. Allegranzi, B. et al. Burden of endemic health-care-associated infection in developing countries: systematic review and meta-analysis. Lancet (London, England) 377, 228–241 (2011).
9. Lundberg, P. W. et al. Pre-Operative Antisepsis Protocol Compliance and the Effect on Bacterial Load Reduction. Surg.
Infect. (Larchmt). 17, 32–37 (2016).
10. World Health Organization. Global guidelines on the prevention of surgical site infection. (2016). Available at: https:// www.who.int/gpsc/ssi-prevention-guidelines/en/. (Accessed: 1st January 2020)
11. European Centre for Disease Prevention and Control. Surgical site infections. Available at: https://www.ecdc.europa.eu/ en/publications-data/directory-guidance-prevention-and-control/healthcare-associated-infections-0. (Accessed: 2nd December 2019)
12. Health, N. C. C. for W. and C. Surgical Site Infection: Prevention and Treatment of Surgical Site Infection. (2008).
13. Ministry of Health of the Republic of Indonesia. A guideline for infection prevention in healthcare fascilities. (2017). Available at: http://ditjenpp.kemenkumham.go.id/arsip/bn/2017/bn857-2017.pdf. (Accessed: 1st January 2020)
14. Sligl, W. I. & Marrie, T. J. Severe community-acquired pneumonia. Crit. Care Clin. 29, 563–601 (2013). 15. Remington, L. T. & Sligl, W. I. Community-acquired pneumonia. Curr. Opin. Pulm. Med. 20, 215–224 (2014).
16. Montull, B. et al. Predictors of Severe Sepsis among Patients Hospitalized for Community-Acquired Pneumonia. PLoS One 11, e0145929 (2016).
17. Gumus, A. et al. Factors Affecting Cost of Patients with Severe Community-Acquired Pneumonia in Intensive Care Unit.
Turkish Thorac. J. 20, 216–223 (2019).
18. Centers for Disease Control and Prevention. Global Health - Indonesia. (2012). Available at: https://www.cdc.gov/ globalhealth/countries/indonesia/default.htm. (Accessed: 29th December 2019)
19. National report of basic health research (Laporan nasional Riskesdas 2018), Ministry of Health, Republic of Indonesia. 73–7 (2018). Available at: http://labdata.litbang.depkes.go.id/riset-badan-litbangkes/menu-riskesnas/menu-riskesdas/426-rkd-2018. (Accessed: 13th November 2019)
20. Ministry of Health, Republic of Indonesia, Basic health research (Riskesdas 2013). 98–101 (2013). Available at: http://labdata. litbang.depkes.go.id/riset-badan-litbangkes/menu-riskesnas/menu-riskesdas/374-rkd-2013.
21. Anevlavis, S. & Bouros, D. Community acquired bacterial pneumonia. Expert Opin. Pharmacother. 11, 361–374 (2010). 22. Eccles, S. et al. Diagnosis and management of community and hospital acquired pneumonia in adults: Summary of NICE
guidance. BMJ 349, 1–5 (2014).
23. Mandell, L. A. et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin. Infect. Dis. 44 Suppl 2, S27-72 (2007).
24. Woodhead, M. New guidelines for the management of adult lower respiratory tract infections. The European respiratory
journal 38, 1250–1251 (2011).
25. Lim, W. S. et al. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax 64 Suppl 3, iii1-55 (2009).
26. Indonesian Society of Respirology. Guideline for diagnosis and management of community pneumonia in Indonesia. (2003). Available at: https://www.scribd.com/doc/125419923/Pnemonia-Komuniti-Pdpi. (Accessed: 22nd April 2019) 27. File, T. M. Community-acquired pneumonia. Lancet (London, England) 362, 1991–2001 (2003).
28. Purba, A. K. et al. Multidrug-Resistant Infections Among Hospitalized Adults With Community-Acquired Pneumonia In An Indonesian Tertiary Referral Hospital. Infect. Drug Resist. 12, 3663–3675 (2019).
29. Farida, H. et al. Viruses and Gram-negative bacilli dominate the etiology of community-acquired pneumonia in Indonesia, a cohort study. Int. J. Infect. Dis. 38, 101–107 (2015).
30. European Centre for Disease Prevention and Control (ECDC). Healthcare-associated infections: surgical site infections. 1–18 (2017). Available at: https://www.ecdc.europa.eu/sites/default/files/documents/AER_for_2017-SSI.pdf. (Accessed: 26th December 2019)
31. European Centre for Disease Prevention and Control (ECDC). Healthcare-associated infections: surgical site infections. 1–15 (2016). Available at: https://www.ecdc.europa.eu/sites/default/files/documents/AER_for_2016-SSI_0.pdf. (Accessed: 26th December 2019)
CHAPTER 2
The burden and costs of sepsis and
reimbursement of its treatment in a
developing country: An observational
study on focal infections in Indonesia
Abdul Khairul Rizki Purba Nina Mariana
Gestina Aliska Sonny Hadi Wijaya Riyanti Retno Wulandari Usman Hadi
Hamzah
Cahyo Wibisono Nugroho Jurjen van der Schans Maarten J. Postma
ABSTRACT
Objectives: This study aimed to determine the burden of sepsis with focal infections in the
resource-limited context of Indonesia and to propose national prices for sepsis reimbursement.
Methods: A retrospective observational study was conducted from 2013-2016 on cost of surviving
and non-surviving sepsis patients from a payer perspective using inpatient billing records in four hospitals. The national burden of sepsis was calculated, and proposed national prices for reimbursement were developed.
Results: Of the 14,076 sepsis patients, 5,876 (41.7%) survived and 8.200 (58.3%) died. The mean
hospital costs incurred per surviving and deceased sepsis patient were US$1,011 (SE +23.4) and US$1,406 (SE +27.8), respectively. The national burden of sepsis in 100,000 patients was estimated to be US$130 million. Sepsis patients with multifocal infections and a single focal lower-respiratory tract infection (LRTI) were estimated as being the two with the highest economic burden (US$48 million and US$33 million, respectively, within 100,000 sepsis patients). Sepsis with cardiovascular infection was estimated to warrant the highest proposed national price for reimbursement (US$4,256).
Conclusions: Multifocal infections and LRTIs are the major focal infections with the highest burden
of sepsis. This study showed varying cost estimates for sepsis, necessitating a new reimbursement system with adjustment of the national prices taking the particular foci into account.
INTRODUCTION
Sepsis is estimated to involve 31.5 million cases each year worldwide.1 Of these cases, 19.4 million are characterized by severe sepsis, accounting for 5.3 million deaths annually.1 These estimates are derived from data compiled for high-income countries. However, the highest mortalities occur in low-income countries, followed by low-middle income countries (LMICs).2 There is a surprising lack of data on mortality and costs among sepsis patients in LMICs, such as most African and Asian countries, including Indonesia.1,3 Indonesia, which is the most populated country in Southeast Asia and the fourth most populated country globally, has a high incidence of communicable diseases.4,5 Ascertaining the granularity of the sepsis burden in Indonesia has become essential in light of the government’s introduction of a new national health insurance system (Jaminan Kesehatan Nasional).6 In 2018, universal health coverage (UHC), provided by a single national payer, became available for 203 million people.7 During the period 2019-2020, coverage will be extended to the entire Indonesian population (approximately 264 million people).4,7 Accordingly, a national reimbursement price for each disease will need to be accounted for within the reimbursement system.7–9
The economic burden of sepsis, which includes providing medication and fluid resuscitation during hospitalization, has been reported to be very high.10 In the United States, hospitalization costs for sepsis patients were approximately US$20 billion in 2011.11 A previous systematic review, which mostly included studies performed in the United States, revealed that an essential analysis of the economic burden of sepsis concerned an evaluation between survivors and non-survivors, because of a major difference in the mean total hospital costs per day (US$351 vs. US$948, respectively).12 The difference in burden between survivors and non-survivors is unknown in LMICs. International budgetary guidelines for sepsis management mostly apply to developed countries and therefore may require cost adjustments of service bundles relating to sepsis management in resource-limited settings.13,14
A focal infection terminology was firstly introduced in 1910 by William Hunter, who elaborated the relationship between focal infections and systemic diseases.15 A focal infection is a potential source of microorganisms that may disseminate into deep tissue and spread to the bloodstream. A further impact of the dissemination of the microorganisms and their toxin in the bloodstream is activation of the inflammatory mediators and worsening organ dysfunction due to sepsis.16 According to the third consensus definitions for sepsis and septic shock17, sepsis has at least an underlying focal infection as an entry of the pathogen to the systemic circulation. Each focal infection causing sepsis comes with different complications, with a wide range of costs. Therefore, the reimbursement of sepsis needs cost adjustments according to the underlying focal infection. In Indonesia, sepsis and the associated focal infections are not coded together when calculating the national price of diseases, resulting in possible under-budgeting for sepsis-related expenditure.18 Therefore, a reevaluation of the costs for sepsis has become urgent for countries like Indonesia, including dealing with underlying focal infections. This study analyzed costs for surviving and deceased sepsis patients, explicitly considering underlying focal infections. In addition, it then estimated national prices for reimbursement under UHC based on the analyzed burden and costs of sepsis.
METHODS
Study designA retrospective observational study was conducted on patients with sepsis in four Indonesian medical centers: (1) Dr. Soetomo General Academic Hospital in Surabaya, a national healthcare referral center, with 1,514 beds, serving eastern Indonesia; (2) Universitas Airlangga Hospital in Surabaya, a teaching medical center with 180 beds in Surabaya; (3) The Prof. Dr. Sulianti Saroso National Center for Infectious Diseases Hospital, with 180 beds in Jakarta; and (4) Dr. M. Djamil Hospital in Padang, a national referral center with 800 beds, serving western Indonesia. Inpatient registries and hospital discharge data were obtained from the Department of Medical Records for the period 01 January 2013 to 31 December 2016. The dataset covered patients demographics, diagnoses, hospital-discharge mortalities, laboratory tests, and medications.
Criteria for selecting patients
All patients with sepsis and aged > 18 years were included. The diagnosis of sepsis was clarified by the physicians. Previously, in Indonesia, the physician used sepsis criteria based on International Sepsis Definition Conference 2001 supported by the Society of Critical Care Medicine, the European Society of Intensive Care Medicine, the American College of Chest Physicians, the American Thoracic Society and the Surgical Infection Society.19 The pathophysiology of sepsis has systematically defined from systemic inflammatory response syndrome (SIRS) to shock sepsis. SIRS was defined at least two of the following clinical signs: the body temperature < 36oC or >38oC, tachycardia (heart rate > 90beats/min), tachypnoea (>20 breaths/min or PaCO2 <30 mmHg or with mechanical ventilation), white blood cells <4,000 cells/µL or >12,000 cells/µL or >10% of band forms.20 Sepsis was defined as SIRS with focal infections.21 Severe sepsis was defined as sepsis with organ dysfunctions or hypoperfusion (oliguria, lactic acidosis, acute mental status alteration) or sepsis-induced hypotension (systolic blood pressure lower 90mmHg). In addition, septic shock is defined as severe sepsis with a condition which requires vasopressor administration after adequate fluid resuscitation.17 In 2016 and afterwards, the criteria for sepsis diagnosis followed the Indonesian Ministry of Health adopted Third International Consensus Definitions for Sepsis and Shock, Sepsis-3 17, and diagnostic criteria for sepsis entailed in the Sequential Organ Failure Assessment (SOFA) score that includes at least two of the following three ‘quick’ SOFA (qSOFA) criteria: systolic blood pressure ≤ 100 mmHg, respiratory rate ≥ 22 breaths per minute, and incorporating altered mentation (Glasgow Coma Scale score < 15).22 In this study, the source infection of sepsis was pointed as focal infection.
The study categorized single focal infections per site of the infections as cardiovascular infections (CVIs), gastrointestinal tract infections (GTIs), lower-respiratory tract infections (LRTIs), neuromuscular infections (NMIs), urinary tract infections (UTIs), and wound infections (WIs). WIs recognized at the sites of surgery were subclassified as surgical site infections (SSIs). The physicians confirmed SSI diagnoses according to the Centers for Diseases Control and Prevention.23 Focal mouth and dental infections were included in the NMI category since those infections anatomically
involved soft tissues such as nerves and muscles. Sepsis patients with two or more focal infections were grouped into sepsis with multifocal infections. Moreover, an unspecified focal infection was labeled as an unidentified focal infection (UFI). The International Classification of Diseases version 10 was applied to determine and record focal infections (see supplement 2.1).
Cost calculation
Cost was analyzed from a payer perspective using billing records that included the costs of beds, drugs, laboratory and radiology procedures, other medical facilities, and total costs. Bed costs encompassed hospital administration fees, daily room services, nursing and medical staff care, and technicians’ services. Drug costs were extracted from the pharmacy department’s budget that covered expenses relating to drugs, fluids, blood products for transfusion, disposable devices, mechanical ventilators, oxygen therapy, and pharmacy services. Physiotherapists’ – as rehabilitation specialists – consultancy costs were recorded and considered under patients bed service costs. Costs for administrations, patient transfer, and ambulance, and other expenses were included in the costs for other medical facilities. The hospitalization costs per admission were analyzed, considering the day spent in an intensive care unit (ICU), presence of SSIs, types of focal infections, and whether the patient survived or not. The 2016 currency exchange rate (US$1 = 13,308.33 IDR) was used, as applied by the Organization for Economic Cooperation and Development (OECD) to convert Indonesian Rupiahs (IDR) into US Dollars (US$)24, with inflation rates of 6.40% for 2013, 6.42% for 2014, 6.38% for 2015, and 3.53% for 2016.25 The economic burden of sepsis was assessed according to the distribution of disease incidence over focal infections and the mean cost of each focal infection using a denominator of 100,000 patients with sepsis.26
Extrapolation of the cost to the national level
The national costs for sepsis were analyzed based on the rates defined by the Indonesian Health Ministry for Indonesia Case Base Groups (INA-CBGs). The INA-CBGs’ rates were used as national projections for extrapolating the sepsis costs – obtained from patient’s billing records – into Proposed National Prices (PNPs) for sepsis reimbursements by considering the following four aspects.18 The first aspect concerned the room classes in the hospital, which were divided into three classes. Class I, patients had more privacy within one room, accommodating up to two patients. Class II accommodating three or four people; Class III service accommodating five or six people in a room.18,27 This study provided the PNP in Class III as the reference. It calculated the actual costs from Classes I, II, and III ) ( CP )– obtained from patient’s billing records – and divided them by the specific factor (α) according to the INA-CBGs at 1.4, 1.2, and 1.0, respectively.18
The second aspect concerned the private or public sector ownership of the hospital. In the INA-CBG system, reimbursement provided by the government through subsidies was 1.03 (β) times higher for private healthcare services compared with the public healthcare services.18 The third and fourth aspects concerned the type of hospital and the region where the hospital is located, to correspond with the specific INA-CBG prices (ICPy) that were published by the Indonesian Ministry of Health in 2016.18 The classification of hospital type in Indonesia was categorized into types A,
26
B, C and D on the basis of the medical specialist services (see Supplement 2.2).18,27,28 There were five INA-CBG regions covering 34 provinces in total (Figure 2.1).18 The ICP for the Hospital Type A in Region I was used as the denominator reference for ICP in the calculation of a PNP, since the actual costs were obtained from the hospitals with type A located in the INA-CBG Region I. Eventually, for a particular focal infection inpatient, in a class of room, in a specific type of hospital in a certain region under the private or the public sectors, a PNP for sepsis with an x focal infection was defined as in the following Formula 2.1:
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8+:9'7";7*:"='*88"M,+=7"!"#
$$$$HO"2)7"8M7=+K+="K*=23,"GvH"3K"7*=)"5'*88",33;O"2)7"8M7=+K+="AF#@5EN"
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.HO"*:%"2)7"9367,:;7:2"8&$8+%?"K*=23,"GwH<""
"
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Formula 2.1 The four aspects for developing a PNP were the mean actual costs reflecting the single mean class price( CP ), the specific factor (α) of each Class room, the specific INA-CBG prices (ICPy), and the government subsidy factor (β).
This study developed 280 PNPs (seven focal infections, four types of hospitals, two sectors, and five regions) for reimbursement of sepsis with particular focal infections in the five INA-CBG regions. To compare with the reference ICPs, the PNPs were categorized into three groups: those with a small difference with the ICP of <US$500, a medium difference of US$500 - 1,000, and a major difference >US$1,000.
Figure 2.1 The five regions covered in the Indonesia Case Base Group (INA-CBG) system. Region 1 (in green) comprises Banten, Jakarta, West Java, Central Java, Yogyakarta, and East Java. Region 2 (in blue) comprises West Sumatra, Riau, South Sumatra, Lampung, Bali, and West Nusa Tenggara. Region 3 (in red) comprises Aceh Darussalam, North Sumatra, Jambi, Bengkulu, Bangka Belitung, Riau Islands, West Kalimantan, North Sulawesi, Central Sulawesi, Southeast Sulawesi, West Sulawesi, South Sulawesi, and Gorontalo. Region 4 (in yellow) comprises South Kalimantan, East Kalimantan, North Kalimantan, and Central Kalimantan. Region 5 (in purple) comprises East Nusa Tenggara, Maluku, North Maluku, Papua, and West Papua. The map was created in mapchart.net.
Statistical analyses
Data were analyzed using IBM SPSS statistics 25, providing descriptive data on baseline characteristics in percentages. Chi-square tests were performed to determine the differences between surviving and deceased sepsis patients. 1,000 samples were bootstrapped, and in cases where the data were overly skewed, the standard error (SE) was adjusted for the mean cost. An Independent Sample T-test was applied to evaluate the statistical cost difference between the surviving and deceased patient groups. Subgroup analyses of hospitalization costs relating to ICU treatment, having SSIs, and types of focal infections were performed. Statistical significance was defined when the p-value was < 0.05.
RESULTS
Of the 14,076 patients with sepsis, 5,876 (41.7%) survived and 8,200 (58.3%) died. The patients were predominantly male (53%). The average age among all patients was 49.4 (+18.9) years. Surviving and deceased sepsis patients evidenced statistical differences for the following single focal infections: LRTIs (38% vs. 62%, respectively, p <0.001), UTIs (56% vs. 44%, respectively, p <0.001), and WIs (18% vs. 82%, respectively, p <0.001). Thirty-one percent of the sepsis patients were diagnosed with multifocal infections with a significant difference between surviving and deceased patients (40% vs. 60%, respectively, p <0.001). Of the 2,138 sepsis patients with SSIs, 74.2% died. Also, patients with sepsis who were hospitalized in an ICU demonstrated a high case fatality rate (69%). Table 2.1 presents a summary of the clinical characteristics of surviving and deceased sepsis patients.
Table 2.1. Baseline characteristics of surviving and deceased sepsis patients
Characteristics (n=14,067)All cases % Survivors (n=5,876) % Deceased (n=8,200) % p-value
Sex
Male 7,467 53.0 3,115 41.7 4,352 58.3 0.943
Female 6,609 47.0 2,761 41.8 3,848 58.2
Aged >60 years 1,638 11.6 626 38.2 1,012 61.8 0.002
Single focal infections
CVI 110 0.8 39 35.5 71 64.5 0.179 GTI 1,328 9.4 565 42.5 763 57.5 0.534 LRTI 3,932 27.9 1,486 37.8 2,446 62.2 <0.001* NMI 368 2.6 153 41.6 215 58.4 0.947 UTI 1,348 9.6 755 56.0 593 44.0 <0.001* WI 1,049 7.5 191 18.2 858 81.8 <0.001* Multifocal infections 4,304 30.6 1,700 39.5 2,604 60.5 <0.001* UFI sepsis 1,637 11.6 987 60.3 650 39.7 <0.001* Having SSIs 2,138 15.2 551 25.8 1,587 74.2 <0.001* ICU 4,297 30.8 1,328 30.9 2,969 69.1 <0.001*
Note: CVI = cardiovascular infections, GTI = gastrointestinal tract infection, ICU = intensive care unit, LRTI = lower-respiratory tract infection, NMI = neuromuscular infection, SSI = surgical site infection, UFI = unidentified focal infection, UTI = urinary tract
Hospitalization costs
The costs per admission for surviving and deceased sepsis patients were, respectively, US$1,011 (+23.4) and US$1,406 (+27.8) (i.e., a difference of US$396, p <0.001). The mean cost for all sepsis cases was US$1,253 (+19.4). Among non-ICU sepsis patients, the average cost was lower for surviving patients (US$960 [+24.3]) compared with that of deceased patients (US$1,189 [+23.6]) per admission (p <0.001). For ICU sepsis patients, the cost per admission was US$1,618 (+47.9), with respective mean costs of US$1,187 (+61.7) and US$1,785.5 (+56.3) for surviving and deceased patients (p <0.001). The cost incurred for patients with sepsis who had SSIs was higher compared with that incurred for patients who did not have SSIs (US$2,938 vs. US$926). Table 2.2 shows these costs divided into unit costs for beds, laboratory and radiology, pharmacy, and other medical facilities.
The national burden of sepsis
The analyses of the treatment costs per admission for sepsis patients with focal infections (see Table 2.2) indicated that the cost was highest for sepsis patients with CVIs (US$1,731), followed by those with WIs (US$1,703), multifocal infections (US$1,584), LRTIs (US$1,122), NMIs (US$986), UTIs (US$748), and GTIs (US$720). The national burden of sepsis revealed a total budget of US$130 million (+US$5,7 million) per 100,000 patients. Sepsis with multifocal infections had the highest national burden of disease within 100,000 sepsis patients (US$48 million), followed by sepsis with LRTIs (US$33 million), UFIs (US$15 million), UTIs (US$11 million), GTIs (US$10.7 million), WIs (US$8.6 million), NMIs (US$2.7 million), and CVIs (US$0.9 million). Figure 2.2 depicts the economic burden of sepsis with focal infections.
Figure 2.2 The economic burden of sepsis with particular focal infections for 100,000 patients with survived (in green) and deceased (in blue).
Note: CVI = cardiovascular infections, GTI = gastrointestinal tract infection, LRTI = lower-respiratory tract infection, NMI = neuromuscular infection, UFI = unidentified focal infection, UTI = urinary tract infection, and WI = wound infection.
Table 2.2 Hospitalization costs for sepsis patients per admission (in 2016 US$)
Hospitalization cost mean(SE)All cases mean(SE)Survived Deceasedmean(SE) Cost difference p-value
Non-ICU stay
Bed costs 222.12(3.72) 196.31(5.17) 242.16(4.95) 45.85(7.49) <0.001
Laboratory and radiology
costs 327.29(6.24) 276.49(8.65) 366.49(8.28) 90.01(12.55) <0.001
Pharmacy costs 404.61(7.15) 369.76(10.37) 431.74(9.53) 61.98(14.40) <0.001
Other medical facilities costs 142.14(2.30) 126.49(3.24) 154.29(3.07) 27.80(4.64) <0.001
ICU stay
Bed costs 330.29(9.81) 243.08(13.05) 364.27(11.52) 121.19(21.76) <0.001
Laboratory and radiology
costs 416.60(14.29) 297.47(18.40) 462.711(16.77) 165.25(31.74) <0.001
Pharmacy costs 662.612(20.59) 491.54(26.36) 729.47(24.19) 237.93(45.64) <0.001
Other medical facilities costs 207.33(6.07) 151.53(7.56) 229.08(7.12) 77.56(13.45) <0.001
Having SSIs
No 925.92(13.13) 838.59(19.75) 988.55(17.18) 149.96(26.58) <0.001*
Yes 2,937.89(88.80) 2,595.84(133.88) 3,042.17(101.32) 446.33(209.61) 0.033*
Types of focal infections
CVI 1,731.09(90.18) 1,634.30(168.91) 1,750.87(98.95) 116.57(240.24) 0.628 GTI 719.76(25.12) 618.06(33.50) 792.711(32.77) 174.65(50.70) 0.001* LRTI 1,122.47(29.76) 818.83(30.51) 1,306.77(37.42) 487.94(60.88) <0.001* NMI 985.62(73.65) 855.84(101.65) 1,076.29(95.69) 220.45(149.21) 0.140 UTI 747.83(29.81) 733.51(41.95) 765.31(44.42) 31.81(59.91) 0.595 WI 1,702.58(221.88) 1,579.36(264.01) 1,765(272.84) 186.60(468.17) 0.690 Multifocal infections 1,583.51(19.36) 1,363.16(51.83) 1,723.78(56.05) 395.64(39.58) <0.001* UFI 1,268.26(65.14) 1,315.27(84.09) 1,197.25(102.94) 118.02(133.11) 0.375
Note: CVI = cardiovascular infections, GTI = gastrointestinal tract infection, ICU = intensive care unit, LRTI = lower-respiratory tract infection, NMI = neuromuscular infection, SSI = surgical site infection, SE = standard error, UFI = unidentified focal infection, UTI = urinary tract infection, and WI = wound infection.
*Statistically significant, p < 0.05
The prospective national price for sepsis patients
The lowest price within the INA-CBG system (ICP) was for UFI sepsis with the ICP at US$298 in a type D public hospital in Region 1, for which a PNP of US$803 was estimated (difference: US$505). The highest PNP was for sepsis with CVIs in type A private hospitals in Region 5 (US$4,256), compared with the ICP of US$2,270 (difference: US$1,986). A remarkable difference between the PNP and ICP was evident for healthcare services relating to sepsis with WIs in type A private hospitals in Region 5 (US$3,995 vs. US$1,421; difference: US$2,574). Reimbursement levels under the overall PNP for sepsis were higher for all types of private hospitals compared with those for public hospitals (all types) in all INA-CBG regions. Out of 280 PNPs, 87 (31.1%) had major differences from the reference ICPs (>US$1,000). PNPs with a major difference were predominantly for reimbursement of sepsis with WIs (Table 2.3). Supplement 2.3 presents the details between the PNPs and the rates specified for the ICPs for sepsis with focal infections in all five regions of Indonesia.
Ta ble 2.3 T he p ro po sed na tio na l p ric e per pa tient fo r sep
sis with foca
l infectio ns in a ll fiv e r egio ns of Indo
nesia (in 2016 US$)
Re gio nal H osp ita l S ep si s w ith G TI S ep si s w ith N M I S ep si s w ith U TI U FI sep si s S ep si s w ith L RT I S ep si s w ith C VI Se psi s w ith W I* Re gi on 1 P ub lic A 1 ,2 96 .9 1 ,77 0.9 2 ,0 84 .1 1 ,7 21 .0 3 ,0 23 .6 3 ,8 97. 8 3 ,6 59 .4 P riv at e A 1, 33 5.9 1 ,8 24 .1 2 ,14 6. 7 1 ,77 2. 6 3 ,11 4. 3 4 ,014 .7 3 ,76 9. 2 P ub lic B 1 ,0 03 .8 1 ,2 39 .3 1 ,3 46.6 1 ,2 04 .3 1 ,75 4. 6 2 ,7 27 .7 2, 65 4.4 P riv at e B 1, 03 3. 9 1, 27 6. 5 1, 32 9.9 1 ,2 40 .5 1 ,8 07. 2 2 ,6 68 .6 2 ,73 4. 0 P ub lic C 80 6. 2 9 95. 3 1 ,17 2.1 9 67. 2 1 ,59 4. 7 2, 11 8.4 2 ,2 81 .1 P riv at e C 83 0. 3 1 ,0 25 .2 1 ,2 07. 2 9 96 .2 1 ,6 42 .6 2 ,18 1.9 2 ,34 9. 6 P ub lic D 6 69. 8 8 27. 0 1 ,019 .4 80 3.6 1 ,3 95 .4 1 ,8 20 .1 1 ,77 0. 4 P riv at e D 6 89. 9 8 51 .8 1 ,050 .0 8 27. 7 1 ,43 7.2 1 ,8 74 .7 1 ,8 23 .5 Re gi on 2 P ub lic A 1, 30 8. 6 1 ,78 6.9 2 ,10 2.9 1 ,7 36 .5 3 ,050 .8 3 ,932 .9 3 ,6 92 .4 P riv at e A 1 ,34 7.9 1 ,8 40 .5 2 ,16 6. 0 1 ,788. 5 3 ,14 2. 3 4 ,050 .9 3 ,8 03 .2 P ub lic B 1 ,012 .8 1, 25 0. 5 1 ,30 2. 8 1 ,215 .2 1 ,77 0. 4 2 ,75 2. 2 2 ,67 8. 3 P riv at e B 1 ,0 43 .2 1 ,2 88. 0 1 ,34 1.9 1 ,2 51 .6 1 ,8 23 .5 2 ,83 4. 8 2 ,75 8. 6 P ub lic C 8 13 .4 1, 00 4. 3 1, 18 2. 6 9 75 .9 1 ,6 09 .1 2 ,13 7.4 2 ,3 01 .7 P riv at e C 8 37. 8 1 ,0 34 .4 1 ,21 8.1 1 ,0 05 .2 1 ,6 57. 3 2 ,2 01. 6 2 ,37 0. 7 P ub lic D 6 75 .8 83 4. 4 1 ,0 28 .6 8 10 .8 1 ,4 07 .9 1, 83 6. 5 1, 78 6. 3 P riv at e D 6 96 .1 8 59 .4 1 ,0 59 .4 83 5. 2 1 ,45 0. 2 1 ,8 91 .6 1 ,8 39 .9 Re gi on 3 P ub lic A 1 ,312 .5 1 ,79 2. 2 2 ,10 9. 2 1 ,741 .6 3 ,0 59 .8 3 ,9 44 .6 3 ,70 3. 4 P riv at e A 1, 35 1.9 1 ,8 46 .0 2, 17 2.4 1 ,79 3.9 3 ,15 1.6 4 ,0 62 .9 3 ,8 14 .5 P ub lic B 1 ,015 .8 1 ,2 54 .2 1 ,3 06 .7 1 ,21 8.8 1 ,7 75 .6 2, 76 0.4 2, 68 6. 3 P riv at e B 1, 04 6. 3 1 ,2 91 .8 1 ,34 5.9 1 ,2 55 .3 1 ,8 28 .9 2 ,8 43 .3 2 ,76 6. 9 P ub lic C 8 15 .8 1 ,0 07. 2 1 ,18 6.1 97 8. 8 1 ,613 .9 2 ,14 3. 8 2 ,3 08. 5 P riv at e C 8 40. 3 1 ,0 37. 4 1, 22 1.7 1, 00 8. 2 1 ,66 2. 3 2 ,2 08 .1 2 ,37 7.8 P ub lic D 6 77. 8 8 36 .9 1 ,0 31 .6 8 13 .3 1 ,412 .1 1 ,8 41 .9 1 ,79 1.6 P riv at e D 69 8. 2 8 62 .0 1 ,0 62 .6 8 37. 7 1 ,45 4. 5 1 ,8 97. 2 1 ,8 45 .4
Re gio nal H osp ita l S ep si s w ith G TI S ep si s w ith N M I S ep si s w ith U TI U FI sep si s S ep si s w ith L RT I S ep si s w ith C VI Se psi s w ith W I* Re gi on 4 P ub lic A 1 ,3 32 .0 1 ,8 18 .8 2, 14 0.4 1 ,76 7.4 3 ,10 5. 2 4 ,0 03 .0 3 ,75 8. 3 P riv at e A 1 ,37 1.9 1 ,8 73 .3 2 ,20 4. 6 1 ,8 20 .4 3 ,19 8. 4 4 ,12 3.1 3 ,8 71. 0 P ub lic B 1 ,0 30 .9 1 ,2 72 .8 1 ,32 6.1 1 ,2 36 .9 1 ,8 02 .0 2, 80 1.4 2 ,7 26 .1 P riv at e B 1 ,0 61 .8 1 ,311 .0 1 ,3 65 .9 1 ,2 74 .0 1 ,8 56 .0 2, 88 5.4 2 ,8 07. 9 P ub lic C 8 27. 9 1, 02 2. 2 1 ,2 03 .7 9 93 .3 1 ,6 37. 8 2 ,17 5. 6 2 ,34 2. 7 P riv at e C 6 87. 9 8 49. 3 1 ,0 46. 9 82 5. 3 1 ,43 3.1 2 ,10 3.1 1 ,8 18 .2 P ub lic D 6 87. 9 8 49. 3 1, 04 6. 9 82 5. 3 1 ,43 3.1 1 ,8 69 .2 1 ,8 18 .2 P riv at e D 70 8. 5 8 74 .8 1 ,07 8. 3 8 50 .1 1 ,47 6.1 1 ,92 5. 3 1 ,8 72 .7 Re gi on 5 P ub lic A 1 ,374 .8 1 ,8 77. 2 2 ,2 09. 2 1, 82 4. 2 3, 20 5. 0 4 ,13 1.7 3 ,87 9. 0 P riv at e A 1 ,41 6. 0 1 ,93 3. 5 2 ,2 75 .5 1 ,8 78 .9 3 ,3 01 .1 4 ,2 55 .6 3 ,9 95 .4 P ub lic B 1 ,0 64 .0 1 ,313 .7 1 ,3 68. 7 1 ,2 76.6 1 ,8 59 .9 2, 89 1.4 2 ,8 13 .7 P riv at e B 1 ,0 95 .9 1 ,3 53 .1 1 ,40 9.8 1 ,31 4.9 1 ,915 .7 2 ,97 8.1 2 ,8 98 .1 P ub lic C 85 4. 5 1 ,0 55 .0 1 ,24 2. 4 1 ,0 25 .2 1 ,6 90 .4 2 ,24 5. 5 2 ,41 8. 0 P riv at e C 8 80 .1 1 ,0 86. 7 1 ,27 9. 6 1 ,0 56. 0 1 ,741 .1 2 ,312 .8 2 ,49 0. 5 P ub lic D 7 10 .0 8 76.6 1 ,0 80 .6 8 51 .8 1 ,47 9.1 1 ,92 9. 3 1 ,8 76.6 P riv at e D 7 31 .3 9 02 .9 1 ,11 3. 0 8 77. 4 1 ,5 23 .5 1 ,9 87. 2 1 ,93 2.9 *I nc lu di ng sur gi ca l s ite inf ec tio ns N ote: T he co lo rs in di ca te th e di ffe re nc e be tw ee n th e PN P fo r s ep sis w ith fo ca l i nf ec tio ns w ith th e ra te s sp ec ifi ed fo r t he IN A-CB G s ( th e gr ee n in di ca te s a gr ou p of lo w PN Ps w ith a sm al l d iffe re nc e (< US $5 00 ), t he b lu e i nd ic at es a g ro up o f m id dl e P N Ps w ith a m ed iu m d iffe re nc e ( S$ 5 00 a nd U S$ 1 ,0 00 ), a nd t he r ed i nd ic at es a g ro up o f h ig h P N Ps w ith a m aj or d iffe re nc e ( >U S$ 1, 00 0) ). T he co m pa ris on b et w ee n P N P a nd I N A-CB G r at es i s p rov id ed i n S up pl em en t 3 . CV I = c ar di ov as cu la r i nf ec tio ns , G TI = g as tro in te st in al t ra ct i nf ec tio n, I CU = i nt en sive c ar e u ni t, I N A-CB G s = I nd on es ia C as e B as e G ro up s, L RT I = l ow er -re sp ira to ry t ra ct i nf ec tio n, N M I = ne ur om us cul ar inf ec tio n, P NP = p ro po se d na tio na l p ric e, U FI = un id en tifi ed fo ca l i nf ec tio n, U TI = ur inar y t ra ct inf ec tio n, an d W I = w oun d i nf ec tio n.
2
DISCUSSION
In this study, the economic burden for focal infections associated with sepsis was comprehensively determined in the resource-limited setting, in Indonesia. Sepsis was mostly induced by LRTIs, accounting for the high associated total cost per patient. Besides LRTIs, the findings indicated a strong correlation between high costs and having SSIs. The costs especially increased for patients with multifocal infections. In the broader scale, the economic burden of sepsis with focal infections was higher for deceased patients than for surviving patients. In the new Indonesian UHC system, the reimbursement for sepsis entails four aspects: class of patient’s room, government subsidies, type of hospital, and the INA-CBG region. Moreover, the current findings show the great difference in costs between PNP and ICP especially for sepsis-related costs with the focal infections of WIs and CVIs.
There is convincing evidence of a positive correlation between LRTIs and sepsis with regard to mortality outcome.29 Over the last decade, LRTIs have been the most prevalent communicable disease in Indonesia.30 The economic burden of sepsis with LRTIs in ICUs in a developing country such as Turkey was estimated at US$2,722 per patient.31 In addition, LRTIs such as community-acquired pneumonia contributes high morbidity in terms of more hospitalizations for ICU admissions, requiring mechanical ventilators, and further sepsis complications.32–34 In addition, elevated hospitalization costs for ICU patients with LRTIs were strongly associated with the use of a mechanical ventilator, presence of severe sepsis and septic shock.31 Confirming these results, some studies have reported that in addition to being induced by LRTIs, sepsis also originates from WIs, GTIs, and UTIs (approximately 16.5%, 16.7%, and 28.3%, respectively).29,35,36 Sepsis arising from GTIs and WIs is mostly associated with surgical wounds.29,37 Infections on the site of surgeries after elective and emergency procedures that contribute to sepsis account for 5.8% and 24.8%, respectively.35 A previous study covering 6.5 million elective surgeries performed in the United States reported an incidence of 1.2% of post-surgical sepsis cases with a high mortality rate of 26%.38 The current data revealed a high case fatality rate of sepsis with SSI. SSI-related costs that include medicines, prolonged length of stay, and readmission could rise to US$22,130 per patient.39
In the current study, sepsis with CVIs presented the highest cost per inpatient but accounted for the lowest national economic burden for sepsis, with focal infections giving relatively low numbers. In a previous systematic review, endocarditis was reported to be a rare disease with costly consequences.40 Sepsis with UTIs, or urosepsis commonly causes kidney dysfunction, leading to high mortality rates. In the current study, the urinary tract ranked third in incidence as an infection site associated with sepsis. The incidence of urosepsis in the United States is about 30% and is higher among women compared with men.41,42 The study was in line with the current findings, where among UTIs the female and male ratio was at 2:1. The incidence of sepsis-associated with multifocal infections remains unknown, particularly in developing countries, but it we found that they are the costliest. Identifying multisource infections with sepsis prior to the occurrence of organ dysfunction is thus an urgent task.43
budget to support private and public healthcare services. In 2016, Indonesia’s health expenditure was approximately US$111.6 billion or 3.1% of its GDP.44 Thus, establishing sufficient healthcare facilities to support the care of sepsis patients is a challenge. According to the National Health Account data published by the OECD in 2016, Indonesia’s inpatient expenditure amounted to IDR158,499.2 billion (or US$11.9 billion).24,44 This expenditure accounts for 40.9% of the country’s national total health expenditure of IDR387,648.5 billion or US$29.1 billion.44 For the sepsis inpatient expenditure, the current findings suggest that the prices in the current INA-CBGs should be upwardly adjusted as well as made specific for infection sites. As a specific item in the INA-CBGs, each individual pays health coverage according to the class of service selected. The service class categories merely relate to the provision of rooms with specific numbers of beds. Therefore, this categorization is ineffective, as all patients receive the same medical services or even when they are placed in ICUs or isolated rooms. Additionally, community healthcare centers, which play an essential role in resource-limited settings in preventing infection complications such as sepsis, could potentially serve as a budget control mechanism by averting hospital infections and then reducing inpatient costs.41
It is believed that this is the first study to assess the burden of disease, incorporating the costs and mortality outcomes of sepsis with focal infections in a resource-limited setting. Notably, it offers a robust methodology for calculating the national price for sepsis based on a consideration of particular focal infections. However, the study had several limitations. First, it did not assess the costs associated with losses in productivity during hospitalization, and indirect costs were not recorded. Moreover, infrastructure costs – such as security systems, parking, and transportation costs – were not included. Second, post-sepsis impact on individual patients’ occupational or educational trajectories, and those of their relatives, was not assessed because the data obtained from the hospitals were not linked to the socioeconomic statuses of individual patients. Third, the national price was modeled with reference to four referral centers. Nevertheless, the resulting national model seemed reasonable. Forth, it was a retrospective study and potential bias could have existed such as misdiagnosis and under-reported focal infections. However, the study was conducted with a big sample size to provide epidemiological and health economic findings that are needed by the Indonesian government for improving the new health insurance system with a resource-limited setting. Last, it did not consider following hospital discharge, particularly for ICU patients. Evidently, the higher mortality rate among sepsis patients after being discharged was a late-onset outcome of their ICU stays.45–47
CONCLUSIONS
It is essential to consider mortality and focal infections in an assessment of the burden of sepsis. Each underlying focal infection determines the particular course of sepsis. In a resource-limited context such as that of Indonesia, where a new UHC system has been introduced, the adequate provision of healthcare services requires a reevaluation and recalculation of the price for sepsis.
Furthermore, in context, sepsis cases with multifocal infections and LRTIs should be categorized as high-burden sepsis cases, reflecting the most obvious examples requiring adjustments to the national price for private and public healthcare services reimbursement.
ETHICAL APPROVAL
The study was approved by the ethical committee of Dr. Soetomo General Academic Hospital, Surabaya (No. 418/Panke.KKE/VII/2017), Airlangga University Hospital (No. 114/KEH/2017), and the National Center of Infectious Diseases at Prof. Dr. Sulanti Saroso Hospital, Jakarta (No. 02/ xxxviii.10/5/2018). The study met the Indonesian governmental requirements on conducting research and the ethical principles for medical research involving human subjects under the Helsinki Declaration.48 All data was deidentified to guarantee patient anonymity.
Abbreviations:
CVI: Cardiovascular infection GTI: Gastrointestinal tract infection IDR: Indonesian Rupiah
ICP: INA-CBG price
ICU: Intensive care unit
INA-CBG: Indonesia Case Base Group LMIC: Low-Middle Income Country LRTI: Lower-respiratory tract infection NMI: Neuromuscular infection
OECD: Organization for Economic Cooperation and Development PNP: Proposed National Price
qSOFA: quick Sequential Organ Failure Assessment SIRS: Systemic inflammatory response syndrome SOFA: Sequential Organ Failure Assessment SSI: Surgical site infection
UHC: Universal health coverage UTI: Urinary tract infection
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